De novo Drug Design and Repurposing to Suppress Liver Cancer via VEGF-R1 Mechanism: Comprehensive Molecular Docking, Molecular Dynamics Simulations and ADME Estimation

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Abstract
Aims: The aim is to halt the progression of liver cancer [Hepatocellular carcinoma] by suppressing the VEGF-R1 receptor using Myricetin and its de novo-designed analogues. Background: VEGF/VEGFR autocrine signalling promotes the growth, progression, and metastasis of Hepatocellular carcinoma, making the development of molecularly targeted therapies highly feasible. Invasive and metastatic behaviours in various cancers, including hepatocellular carcinoma [HCC], are closely monitored through the use of VEGF signalling pathway inhibitors. Specifically in HCC, VEGFR-1 facilitates the invasive capabilities of cancer cells primarily by triggering the epithelial-mesenchymal transition [EMT] process. VEGFR-1 significantly influences the activity of proteolytic enzymes that are critical for the invasive behaviour of HCC cells. Notably, a novel mechanism has been discovered where VEGFR-1 activation leads to the upregulation of MMP-9, thereby enhancing the invasiveness of HCC cells. The scientists, in their study, have elaborated on the various antiangiogenic agents developed for the treatment of HCC. They have highlighted clinical trials that explore the efficacy of these treatments, which include the application of monoclonal antibodies and small-molecule kinase inhibitors designed to target specific pathways involved in tumour angiogenesis and growth. Objective: Creating a pharmaceutical chemistry table regarding ‘’Structure-Activity Relationship of New Compounds on anticancer’’. To do so, Myricetin and its de novo designed structured variants were used in molecular docking, molecular dynamics, cluster analyses, and 1H NMR estimation to specifically understand and enhance the mechanism of suppressing the VEGF-R1 receptor. Methods: Proper ligand [Myricetin and its analogues] and receptor [VEGF-R1] preparations, and optimizations were done using the density functional theory [DFT]/B3LYP function along with the 6-31G[d,p] basis set principle in the latest software programs such as Gaussian 09, Gauss View 6.0 and Avogadro. Then using PyRx and Autodock Vina 1.1.2., many molecular docking trials were achieved with 100 posed simulations in each run. An extensive cluster analysis was performed to identify the most optimal docking poses with the highest accumulation and most favourable binding interactions, ensuring the accuracy of the study. The docking configurations that exhibited the most precise and advantageous binding energies were chosen as initial structured data for subsequent Molecular Dynamics [MD] simulations for each drug candidate. To verify the molecular docking results, MD runs were achieved in our supercomputers and the trajectory analyses were made. The data confirmed what was found in molecular docking results, verifying the high efficiency of the druggable molecules’ inhibition towards VEGF-R1. Results: Amine-derivatized Myricetin has a significantly high docking score [-10.56 kcal/mol] and great inhibition constant compared to pristine Myricetin [-4.77 kcal/mol] itself while Fluorinederivatized Myricetin [-6.45 kcal/mol] has an affinity towards VEGF-R1 between the first two molecules. Thus, the structure-activity relationship concerning pharmaceutical chemistry aspects of all the molecules studied, yielded us a great insight into what Myricetin’s organic structure possesses towards inhibiting the progression of Liver Cancer. Also, ADME studies showed that both Amine and Fluorined-derivatized Myricetin molecules are good drug candidates. Conclusion: This study highlighted the significant potential of Myricetin as an anti-cancer drug when modified with specific functional groups. Through comprehensive in silico computational analyses, our research group enhanced Myricetin's inhibitory capabilities by derivatizing its Hydroxyl group with Amine and Fluorine, resulting in improved docking scores and inhibition constants. The findings from molecular docking and molecular dynamics simulations provide a promising foundation for future in vitro and in vivo investigations of this molecule as a potential drug in cancer research.

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